Enzalutamide, also known as 4-{3-[4-cyano-3-(trifluoromethyl) phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide, is represented by the following structure of Formula I:

Enzalutamide is marketed by Astellas under the trade name XTANDI® is a androgen receptor inhibitor for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.
U.S. Pat. No. 7,709,517 (“the '517 patent”) discloses a variety of diarylhydantoin compounds and their derivatives such as enzalutamide. The '517 patent discloses a process for preparation of enzalutamide by preparation of 4-isothiocyanato-2-trifluoro methyl benzonitrile of Formula 3 from 4-amino-2-trifluoromethyl benzonitrile of Formula 2 using thiophosgene followed by cyclization of the Formula 3 with N-methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-amino benzamide of Formula 4 by microwave irradiation at a temperature of about 100° C. for about 11 hr to obtain enzalutamide, which is purified by silica gel column chromatography with a mixture of methylene chloride:acetone. The process disclosed in the '517 patent is schematically represented as follows:

The synthesis of enzalutamide as disclosed in the '517 patent has certain drawbacks as it involves:                a) preparation of isothiocyanate intermediate of Formula 3 involves highly noxious reagent such as thiophosgene, which is an insidious poison and it generates high amount of poisonous phosgene gas and is difficult to control, particularly on commercial scale and thus requires more labor and utmost care to use;        b) cyclization of compound of formula 3 and formula 4 involves microwave irradiation at 100° C. for a period of about 11 hr gave less yields of about only 25%. The use of special techniques such as reaction by microwave irradiation is not viable for commercial scale operations as this technique involves specialized expensive equipments;        c) further formation of high amounts of un-cyclized impurity of Formula 1A and urea by-product of Formula 3B as an impurities in the cyclization reaction and thus additional purification steps are required to remove; and        
                d) involves tedious chromatographic purifications, which contributes significant impact on the final yield and purity, makes the process not viable for large scale manufacturing.        
Patent publication No. WO2011/106570 (“the '570 publication”) disclosed an alternate process for preparation of enzalutamide by cyclization of 4-isothiocyanato-2-trifluoro methyl benzonitrile of Formula 3 and methyl-2-(3-fluoro-4-(methylcarbamoyl) phenylamino)-2-methylpropanoate of Formula 6 in a mixture of dimethylsulfoxide:isopropyl acetate for a period of about 17.5 hours. The process disclosed in the '570 publication is schematically represented as follows:

The '570 publication also discloses preparation of enzalutamide by coupling of 4-amino-2-(trifluoromethyl) benzonitrile of Formula 2 and 2-{[3-fluoro-4-(methyl carbamoyl) phenyl]amino}-2-methylpropanoic acid of Formula 7 in presence of a coupling reagent EDCl and followed by cyclization in presence of highly noxious thiophosgene. The process disclosed in the '570 publication is schematically represented as follows:

U.S. Pat. No. 8,524,755 (“the '755 patent”) discloses enzalutamide active metabolites such as carboxylic acid enzalutamide derivative of Formula MI, N-desmethyl enzalutamide of Formula MII, oxidative metabolites such as Formula MIII, Formula MIV and Formula MV and its process for preparation thereof.

Patent publication No.(s) WO2015/063720, WO2015/121768, CN103910679, CN103980141, CN104016924 and CN104710367 disclosed process for preparation of enzalutamide by final cyclization of 4-isothiocyanato-2-trifluoro methyl benzonitrile of Formula 3 and methyl-2-(3-fluoro-4-(methylcarbamoyl) phenylamino)-2-methyl propanoate of Formula 6 by the same process disclosed in '570 publication.
Patent publication No. WO2015/092617 (“the '617 publication”) disclosed process for preparation of enzalutamide by cyclization of benzotriazole or succinamide ester intermediate with o-phenyl[4-cyano-3-(trifluoromethyl)phenyl]carbamothioate or 4-isothiocyanato-2-trifluoro methyl benzonitrile in a mixture of dimethylsulfoxide:isopropyl acetate. The process disclosed in the '617 publication is schematically represented as follows:

U.S. publication No. US2015/0210649 (“the '649 publication”) disclosed process for preparation of enzalutamide by cyclization of acid intermediate of Formula 7 with 4-isothiocyanato-2-trifluoro methyl benzonitrile in presence of phenol in chloroform. The process disclosed in the '649 publication is schematically represented as follows:

C.N. publication No. (s) 104803918 (“the '918 publication”) and 104803919 (“the '919 publication”) disclosed process for preparation of enzalutamide by cyclization of diester intermediate with 4-isothiocyanato-2-trifluoro methyl benzonitrile and finally conversion of ester in to N-methyl amide in presence of methylamine. The process disclosed in the above publications is schematically represented as follows:

C.N. publication No. 104844520 (“the '520 publication”) disclosed process for preparation of enzalutamide by reaction of hydantoin intermediate with bromo intermediate at final stage. The process disclosed in the '520 publications is schematically represented as follows:

C.N. publication No. 104844521 (“the '521 publication”) disclosed process for preparation of enzalutamide by cyclization of hydantoin ring at final stage. The process disclosed in the '521 publications is schematically represented as follows:

Based on the drawbacks mentioned above, there is a vital need to develop a process for the preparation of enzalutamide and its intermediates, which is readily amenable to large scale production.
Hence, present inventors focused research to simplify the process for the preparation of enzalutamide, which avoids mainly microwave irradiation and making the process more suitable for commercial applications with higher purity and obviate the problems associated with the reported process as well as avoiding noxious and expensive reagent such as thiophosgene.